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03/05/2104

CROI 2014: Are Any Guidelines-preferred ART Regimens “More Preferred”?


The most recent update of the HHS Guidelines lists 7 regimens using 6 different third agents as preferred for initiation of antiretroviral therapy (ART) in adolescents and adults. Many large randomized trials have been done comparing preferred 3rd agents, most commonly to efavirenz. ACTG 5257 studied 3 regimens from the guidelines-preferred list that do not contain efavirenz [1]. Treatment-naive patients were randomized to open-label treatment with darunavir (DRV) or atazanavir (ATV), both boosted with ritonavir, or raltegravir (RAL), each combined with tenofovir DF/emtricitabine. This was a large study powered to demonstrate equivalence (not non-inferiority) between regimens, defined by the 97.5 CI for differences between regimens falling entirely within a 10% corridor above and below zero. The study included 1809 participants randomized to one of the 3 arms. The primary endpoints were analyzed by time-to-event at week 96. For the endpoint of virologic failure (ACTG definition: viral load >1000 week 16-24 or >200 thereafter), all 3 regimens met criteria for equivalency. The proportion discontinuing randomized therapy for a tolerability or safety issue was 14%, 5% and 1% for ATV, DRV and RAL, respectively. For this endpoint, ATV was not equivalent to the other two agents. Nearly half of ATV discontinuations were for hyperbilirubinemia or jaundice. For the composite endpoint of either virologic or toxicity failure, none of the regimens were equivalent; RAL was favored over either ATV or DRV and DRV was favored over ATV. Alternate analyses also were presented. Using the “snapshot” approach currently favored by the FDA, 80% 73% and 63% in the RAL, DRV and ATV arms, respectively, remained on randomized therapy and had a viral load <50 at week 96, with all differences achieving statistically significant. However, participants who changed randomized therapy were continued on study and when analyzed by intention-to-treat (ITT), ignoring switches, the success rates were higher and the differences between arms were smaller. In this analysis, 94%, 89% and 88%, respectively had a viral load <50. Resistance was uncommon in all arms, but was seen more often in the RAL arm. Triglyceride, total and LDL cholesterol increases were significantly greater with either ATV or DRV than with RAL, but lipid changes in all arms were small and of minor clinical significance [2].

This study provides refined information about differences between 3 guidelines-preferred regimens. It shows raltegravir is better tolerated than than currently preferred boosted protease inhibitors, which are in turn better tolerated than their predecessors in this class. The study design was open label and allowed patients to switch therapy and remain on study. This design created an environment that likely favored a low threshold to switch for adverse events, including medically insignificant but sometimes cosmetically troublesome indirect hyperbilirubinemia due to ATV, which appeared to drive the largest differences between regimens. Other trial designs may create a higher incentive to remain on randomized therapy, but this design may more closely resemble what happens in clinical practice. Perhaps the most telling analysis was the ITT ignoring switches, which suggests that when choosing among 3 very good regimens, the initial regimen choice is less important if adverse events are managed with timely regimen changes.

Reference:
Landovitz RJ, Ribaudo HJ, Ofotokun I, et al. Efficacy and Tolerability of Atazanavir, Raltegravir, or Darunavir With FTC/Tenofovir: ACTG 5257. Abstract 85, CROI 2014, Boston, MA, March 3-6, 2014.
Ofotokum I, Ribaudo H, Na L, et al. Darunavir or Atazanavir vs Raltegravir Lipid Changes Are Unlinked To Ritonavir Exposure: ACTG 5257 Abstract 746, CROI 2014, Boston, MA, March 3-6, 2014.


Source: Reporting for PRN News: David H Shepp, MD